We hypothesize that amyloid beta-protein (A-beta) assembly into oligomers and polymers is a seminal[unreadable] neuropathogenetic process in Alzheimer's disease (AD) and in cerebral amyloid angiopathy (CAA).[unreadable] Inhibiting formation of, or disrupting, A-beta assemblies thus could be of benefit in the treatment of these[unreadable] disorders. To test this hypothesis, a detailed mechanistic knowledge of the assembly process is necessary.[unreadable] Our previous work towards this goal revealed the existence of protofibrillar fibrillogenesis intermediates.[unreadable] These have been found to be neurotoxic in vitro. Recently, in collaborative studies with the Lannfelt group,[unreadable] we reported that protofibrils may be the causative agents in an "Arctic" form of AD. Thus, a concordance of[unreadable] results from fundamental studies of A-beta assembly in vitro with those from clinical investigations in[unreadable] humans supports the involvement of prefibrillar assemblies in AD pathogenesis. In order to understand the[unreadable] structural and thermodynamic principles underlying the formation of these toxic A-beta assemblies, rigorous[unreadable] in vitro studies are necessary. This elucidation process should facilitate later rational design and testing of[unreadable] therapeutic agents. Here, we seek to delve deeply into the thermodynamics and structural biology of early[unreadable] A-beta assembly reactions in order to understand the fundamental factors controlling these processes and[unreadable] to identify and characterize the structures formed. These structures include small prenuclear oligomers,[unreadable] larger micelle-like oligomers, fibril nuclei, and protofibrils. Importantly, knowledge gained regarding the[unreadable] kinetics of formation and the stability of these assemblies will be used to enable functional assays of the[unreadable] biological effects of the assemblies. We propose to accomplish these goals in the context of the following[unreadable] four interconnected aims.[unreadable] Aim 1. To elucidate the thermodynamics of A-beta fibril formation at neutral pH.[unreadable] Aim 2. To determine the structural features of early A-beta assemblies.[unreadable] Aim 3. To determine the mechanism of transformation of early A-beta assemblies into fibril nuclei.[unreadable] Aim 4. To determine the biological activity of early intermediates.